Project Summary/Abstract This is the second renewal application for this project to understand the role of genetic changes in the pathogenesis of glomerular diseases like focal segmental glomerulosclerosis (FSGS). In this application, we propose two specific aims. In the first, we propose to characterize a gene that we discovered that is highly expressed in podocytes. This gene, ARHGAP24, is a known regulator of the actin cytoskeleton and the high expression of this gene implicates a specific actin regulatory pathway in the normal function of podocytes. To test the role of this gene in the glomerulus, we propose to generate and characterize a mouse that lacks expression of ARHGAP24. In the second aim, we will set-up a genetic screen that combines RNAi technology and state of the art mouse genetic methods to perform a genetic screen in mouse to identify genes that when mutated contribute with CD2AP and another podocyte specific gene, synaptopodin, in the pathogenesis of glomerular dysfunction. Our long-term goal is the identification of all genes that, when mutated, contribute to the pathogenesis of human FSGS.